The long-term objective of this work is to provide data and insights which can be used to achieve the maximun cariostatic benefits of fluorides. The realization of this objective depends on the characterization of the mechanism responsible for the cariostatic effect. The proposed work is largely based on the hypothesis that systemically derived fluoride is of crucial importance in the action of this ion. Thus, attention wil be focused on those variables of fluoride metabolism which can alter the fluoride levels in, and/or rates of delivery to, the oral environment which includes the developing and matured enamel, the various oral fluids and the subcompartments found therein. Using in situ perfusion of the excretory ducts of the major salivary glands of dogs, we will evaluate the influence of perfusion rate, pH and Mg++ concentration on the ductal handling of fluoride. In vivo studies using rats and graded doses of fluoride will examine the uptake of fluoride by developing enamel and the possible involvement of the enamel organ in this process. We will further examine the possibility of circadian rhythms in plasma fluoride levels and the influence of the blood sampling site on such levels will be evaluated. Preliminary data indicate that the level of physical activity can markedly alter the normal metabolic pattern of fluoride. This variable will be investigated in depth. Concurrently, studies with rats will compare the cariostatic efficacy of systemically derived fluoride (slow-release, ip) with fluoride administered in the drinking water and of pre-eruptive vs. post-eruptive fluoride. Results from these studies will provide a clearer understanding of the determinants of fluoride levels and secretion rates in the saliva, of the impact of several physiologic variables on plasms and intraoral fluoride levels, and of the importance of systemically derived fluoride in the cariostatic action of this ion.